Extracellular vesicles from bone marrow-derived multipotent mesenchymal stromal cells regulate inflammation and enhance tendon healing

Abstract

Background Extracellular vesicles from bone marrow-derived multipotent mesenchymal stromal cells (BMSC-EVs) can play important roles in the repair of injured tissues. However, no reports have investigated the role and underlying mechanisms of BMSCs-EVs in the tendon repair process. We hypothesized that BMSC-EVs may play a role in modulating inflammation during tendon healing and improving tendon repair in a rat model of patellar tendon injury. Methods First, we created window defects in the patellar tendons of Sprague–Dawley rats. Rats (n = 16) were then randomly assigned to three groups: BMSC-EVs group, Fibrin group, and control group. Rats in the BMSC-EVs group were treated with BMSC-EVs and fibrin glue (25 µg in 10 µL). Rats in the fibrin group were treated with fibrin only, and those in the control group received no treatment. Histopathology, immunohistochemistry, and gene expression analyses were performed at 2 and 4 weeks after surgery. Results At 4 weeks, tendons treated with BMSC-EVs showed regularly aligned and compact collagen fibers as compared with the disrupted scar-like healing in rats in the fibrin and control groups. The expression of genes related to tendon matrix formation and tenogenic differentiation: collagen (COL)-1a1, scleraxis (SCX), and tenomodulin (TNMD) was significantly higher in the BMSC-EVs group than in the other two groups. With histopathology, we observed significantly higher numbers of CD146+ tendon stem cells and fewer numbers of apoptotic cells and C–C chemokine receptor type 7 (CCR7)-positive proinflammatory macrophages in the BMSC-EVs group. BMSC-EVs treatment also led to an increase in the expression of anti-inflammatory mediators (IL-10 and IL-4) at 2 weeks after surgery. Conclusions Overall, our findings show that the local administration of BMSC-EVs promotes tendon healing by suppressing inflammation and apoptotic cell accumulation and increasing the proportion of tendon-resident stem/progenitor cells. These findings provide a basis for the potential clinical use of BMSC-EVs in tendon repair.

Extracellular vesicles from rat-bone-marrow mesenchymal stromal/stem cells improve tendon repair in rat Achilles tendon injury model in dose-dependent manner: A pilot study

“…Higher concentrations of MSC-derived EVs performed better than low concentrations and better than MSCs alone. As already shown [9,10,11], three studies have already been published on this topic, but direct comparisons with the present investigations are difficult given the different focus. The three previous studies focused largely on inflammatory mechanisms, and used different methodologies and different types of injury over different time periods.…”

“…Cell-free delivery of bioactive cargos by EV induces the same beneficial responses as stemcell transplantation, offering remarkable benefits over conventional cell-therapy: for example, EVs avoid the risk of tumorigenesis, and heterotopic ossification and calcification [3,4] and are immunologically unresponsive agents [7,8]. Finally EVs play a role in tendon-healing by modulating inflammatory responses [9,10,11].…”

Tendon stem cell-derived exosomes regulate inflammation and promote the high-quality healing of injured tendon

“…Rat tenocyte isolation and culture were performed as previously described by Shi and Wu [17,18]. Briefly, the tendon tissue from rat was cut into small pieces and placed in six-well culture plates.…”

“…The specific surgical methods are similar to those employed in previous studies [17,19]. Briefly, after anesthesia with 0.3% sodium pentobarbital (30 mg/kg, Sigma) in rats, a 2-cm-long incision was made in the right heel of rats to expose the Achilles tendon and remove a third of the central part of the tendon with a surgical blade, resulting in a central defect model of the Achilles tendon.…”

MFG‐E8 regulates inflammation and apoptosis in tendon healing, and promotes tendon repair: A histological and biochemical evaluation

“…The fibrin sealant (Baxter®, Vienna, Austria) used in many kinds of research act as a useful vehicle of growth factors. It could produce a fibrin clot after applied to the tendon window defects …”